Fetal Hyperinsulinemia Research Articles

Fetal growth and hyperinsulinaemia in adult life.

To explore the relation between reduced fetal growth and impaired glucose tolerance in adult life, an oral glucose tolerance test (75 g glucose) was carried out on 218 men and women, now aged around 50 years, who had been measured in detail at birth. Measurements of plasma concentrations of glucose and insulin were made at 0, 30, and 120 min. Fasting plasma concentrations of proinsulin and 32-33 split proinsulin were also measured. People in the highest category of birthweight tended to have the lowest plasma concentrations of insulin as adults at both 0 and 120 min, though both these relations were weak. Plasma insulin concentrations in adult life were more strongly related to abdominal circumference at birth than to birthweight. After adjusting for sex and body mass index, mean insulin concentrations at 0 min fell from 50 pmol l-1 to 46 pmol l-1 (p = 0.04) and at 120 min from 235 pmol l-1 to 144 pmol l-1 (p = 0.003) between people whose abdominal circumference at birth had been less than 11.5 in and those who abdominal circumference had been greater than 13 in. Plasma glucose concentrations at 120 min also fell with increasing abdominal circumference at birth. Because abdominal circumference at birth is an indicator of the growth of the liver in fetal life, one interpretation of these findings is that the sensitivity of the liver to insulin is permanently reduced if the intrauterine development of this organ is impaired.

Fetal growth and hyperinsulinaemia in adult life

To explore the relation between reduced fetal growth and impaired glucose tolerance in adult life, an oral glucose tolerance test (75 g glucose) was carried out on 218 men and women, now aged around 50 years, who had been measured in detail at birth. Measurements of plasma concentrations of glucose and insulin were made at 0, 30, and 120 min. Fasting plasma concentrations of proinsulin and 32-33 split proinsulin were also measured. People in the highest category of birthweight tended to have the lowest plasma concentrations of insulin as adults at both 0 and 120 min, though both these relations were weak. Plasma insulin concentrations in adult life were more strongly related to abdominal circumference at birth than to birthweight. After adjusting for sex and body mass index, mean insulin concentrations at 0 min fell from 50 pmol l−1 to 46 pmol l−1 (p = 0.04) and at 120 min from 235 pmol l−1 to 144 pmol l−1 (p = 0.003) between people whose abdominal circumference at birth had been less than 11.5 in and those who abdominal circumference had been greater than 13 in. Plasma glucose concentrations at 120 min also fell with increasing abdominal circumference at birth. Because abdominal circumference at birth is an indicator of the growth of the liver in fetal life, one interpretation of these findings is that the sensitivity of the liver to insulin is permanently reduced if the intrauterine development of this organ is impaired. © 1998 John Wiley & Sons, Ltd.

Evaluation of Glucose Intolerance in Pregnancy Using Biochemical Markers of Fetal Hyperinsulinemia

We aimed to evaluate gestational impaired glucose tolerance (GIGT) in untreated patients using umbilical cord blood insulin and connecting peptide (C-peptide) concentrations to indicate fetal hyperinsulinemia. A 75 g, 2-hour oral glucose tolerance test, evaluated using WHO criteria, was performed in 722 antenatal patients. Cord C-peptide (p = 0.001) and insulin (p = 0.008) concentrations were significantly higher in patients with GIGT in comparison to those with normal glucose tolerance. The WHO test failed to identify abnormal C-peptide concentrations (p = 0.057), but did identify abnormal insulin concentrations (p = 0.006) and cases where either or both were raised (p = 0.002), with a low Youden’s index (range 8.1–11.3) in all 3 cases. A significant biochemical difference exists in patients with GIGT. The WHO criteria for GIGT predict abnormal biochemical outcomes, but they do so poorly.

Increased macrosomia and perinatal morbidity independent of maternal obesity and advanced age in Korean women with GDM.

To examine the impact of gestational diabetes mellitus(GDM) on perinatal outcome in a setting where influences of maternal age and obesity would be minimal. A case-control study was done to compare the outcome of pregnancy in 65 women with GDM and 153 women with normal carbohydrate metabolism matched for age, height, and prepregnancy weight. The frequencies of preeclampsia and primary cesarean sections were higher and delivery was earlier in pregnancies complicated by GDM. Birth weight, symmetry index, and chest circumference were greater, and macrosomia and need for phototherapy were more common in offspring of mothers with GDM. Cord-serum C-peptide and insulin concentrations were higher in the infants of mothers with GDM and were strongly correlated with birth weight and symmetry index. However, maternal age, prepregnancy weight, and prepregnancy BMI were not correlated with birth weight. Postprandial glucose levels during the first 2 weeks after diagnosis of GDM had associations with the infants' birth weight, symmetry index, and cord insulin concentration in the diet-treated patients with GDM. Antepartum maternal glucose metabolism was significantly associated with fetal hyperinsulinemia and excessive fetal growth in relatively nonobese Korean women. These findings support a direct role for metabolic factors in the adverse outcomes in pregnancies complicated by GDM.

Consequences of an Aberrant Intrauterine Milieu: Metabolic Imprinting.• 1429

Diabetes in pregnancy is associated with an increased risk of obesity and glucose intolerance in children and the development of non-insulin dependent diabetes (NIDDM) in young adults. Genetic predisposition may be one factor leading to this increased risk. However, we suggest that an abnormal metabolic intrauterine milieu alone can predispose offspring to develop glucose intolerance. We have developed a rat model of fetal overgrowth (LGA) and mild fetal hyperglycemia and hyperinsulinemia. Maternal rats are not diabetic. We hypothesized that fetuses exposed to this abnormal intrauterine metabolic milieu would develop glucose intolerance as juvenile pups. In addition, as aberrant hepatic metabolism is a feature of NIDDM, we hypothesized that key components of hepatic metabolism such as glucose transport and glucose phosphorylation would be altered in LGA rat pups. We performed selective ablation of alternate fetuses by uterine artery branch ligation on gestational day 15 (term=21.5)(n=15); litters from sham operated mothers served as controls (C) (n=12). Fetuses were allowed to deliver spontaneously. OGTT's, glucokinase and hexokinase activity, and GLUT 2 protein and mRNA, levels were determined in liver of 21d animals. Body, but not liver weights were higher in LGA animals compared to C (Body: 63.39±1.22 v. 52.3±1.64 g; Liver: 2.07±0.17 v.2.09±0.13 g, LGA vs C, respectively)(p<0.05). Basal glucose (10.91 ±1.11 v 11.79±1.2 mM, LGA v C) and insulin (1.79±0.75 v 1.90±0.63 ng/mL, LGA v C) levels were similar in LGA and C. However, after glucose loading, glucose(19.27±2.1 v 14.47±1.8 mM LGA v C) and insulin levels(4.92±0.45 v 3.00±0.21 ng/mL, LGA v C) were higher in LGA compared to C at 1h (p<0.05). Glucokinase activity was lower in LGA liver(10.09±0.54mU/mg protein/min) compared to C (16.99±0.65 mU/mg protein/min), (p<0.05). LGA Glut 2 protein and mRNA levels were also less than C (45% of C for protein and 20% of C for mRNA) (p<0.01). Immunohistochemistry demonstrated that the intensity of staining for Glut 2 was qualitatively less in LGA liver. In summary, LGA pups had increased body weight, glucose intolerance, decreased hepatic GLUT 2 expression, and decreased hepatic glucokinase activity. Decreased glucokinase activity results in an inability of glucose to suppress hepatic glucose production, and its impairment may contribute to the glucose intolerance observed in these animals. The physiologic consequence of diminished hepatic GLUT 2 levels is unclear. Our results support the hypothesis that transient fetal hyperglycemia and hyperinsulinemia can cause permanent metabolic imprinting after birth.

Circulatory and metabolic effects of alpha-adrenergic blockade in the hyperinsulinemic ovine fetus.

Fetuses of diabetic women exhibit hypoxemia, elevated catecholamine concentrations at birth, and increased incidence of death. Our previous findings suggested that experimental fetal hyperinsulinemia results in a surge in catecholamines with cardiovascular changes supported by increased beta-adrenergic activity. The present experiments were designed to assess the contribution of alpha-adrenergic stimulation to the hemodynamic changes in the hyperinsulinemic ovine fetus. Combined ventricular output, regional organ blood flow, vascular resistance, metabolism, and catecholamine concentrations were measured before and during an infusion of insulin and during continued infusion with alpha-adrenergic blockade (phentolamine) in eight chronically catheterized fetal sheep. Fetal insulin infusion produced hyperinsulinemic-hypoglycemia, a surge in epinephrine and norepinephrine concentration, and increases in the combined ventricular output (blood flow to the fetus plus placenta) and regional blood flow to the fetus, heart, stomach, gastrointestinal tract, fat, and carcass. In the hyperinsulinemic state, alpha-adrenergic blockade was associated with additional increases in fetal norepinephrine concentration and no major changes in combined ventricular output or blood flow to the body of the fetus, except for decreased blood flow to the stomach and lungs, and a decrease in stroke volume. Because vasodilation characterizes the hyperinsulinemic state, alpha-adrenergic stimulation contributes less to compensatory cardiovascular changes in the hyperinsulinemic fetus than that which we previously have shown for beta-adrenergic stimulation.

Short- and long-range complications in offspring of diabetic mothers

The perinatal mortality rate of infants of diabetic mothers (IDMs) has declined dramatically from 250 per 1000 live births in the 1960s to a near-normal 20 per 1000 live births in the 1980s. Five to 8% of all IDMs suffer from major congenital malformations, and it is the latter that are responsible for 50% of these perinatal deaths. It has been shown that tight glycemic control prior to conception and during pregnancy can prevent an excess rate of congenital malformations, fetal macrosomia, birth trauma, and neonatal respiratory distress syndrome. We briefly review the short- and long-range complications that occur in offspring of diabetic mothers (ODMs) from gestation through young adulthood. Short-term neonatal complications, such as hypoglycemia, hypocalcemia, hypomagnesemia, hyperbilirubinemia, and polycythemia, are related mainly to fetal hyperinsulinemia, hypoxemia, and prematurity. They are readily controllable within the setup of modern neonatal intensive care units. Long-range complications include an increased rate of childhood and adolescent obesity, impaired glucose tolerance or diabetes mellitus, and subtle neuropsychological dysfunctions. These may be related to the severity of the maternal hyperglycemia during pregnancy, the consequent fetal hyperinsulinemia, and third trimester maternal lipid metabolism disturbances. Today we have at hand the knowledge and tools to properly treat both pregestational and gestational diabetes. Increased education of the general practitioner and the target population regarding early referral of pregestational diabetic mothers and the implementation of screening programs for gestational diabetes will further reduce diabetic pregnancy-related morbidity.

Management of Gestational Diabetes Mellitus

The clinical significance of gestational diabetes mellitus, or carbohydrate intolerance with onset or first diagnosis during pregnancy, is a subject of debate. 1,2 The concept of gestational diabetes mellitus was popularized before considerations of evidence-based medicine came on the scene. Like many other conditions, gestational diabetes mellitus became a clinical entity without the carefully collected epidemiologic data we now require. Nevertheless, the majority of obstetricians in the United States screen their pregnant patients for this condition. 3 There is a large body of evidence to support the contention that marked maternal hyperglycemia in the range found in patients with preexisting diabetes mellitus can have an adverse impact on fetal growth, development, and well-being. The mechanism appears to be fetal hyperinsulinemia evoked by hyperglycemia. The following questions need to be resolved: (1) How severe must maternal hyperglycemia be to measurably worsen pregnancy outcome? (2) Can we intervene to prevent adverse outcomes?

Intravenous fluid administration in pregnancy: maintenance and acute hydration

AbstractPregnancy is characterised by a hyperdynamic output state, low blood viscosity and haematocrit, reduced blood and tissue buffering capacity, increased tendency to both sodium and water retention, an exaggerated ketotic and hypoglycaemic response to dehydration and increased insensible losses and decreased heat tolerance. These changes are relevant to anaesthetists attempting to restore and maintain fluid, electrolyte, glucose and metabolic balance in labour and during anaesthesia, resuscitation and critical care.Fluid maintenance and replacement in pregnancy follow the basic principle of replacing what is lost in both quantity and quality, remembering the specific requirements of the individual patient and situation.The altered milieu of pregnancy makes the use of most crystalloid containing fluids somewhat controversial particularly for acute hydration (fluid loading) in association with central neural blockage or resuscitation. Normal saline and lactate tend to worsen reduced buffer base capacity and cause further dilution of plasma proteins in an already low blood glucose level, so potentiating the efforts of highlevel epidural or spinal sympathetic blockade. Glucose loads can cause fetal hyperinsulinaemia, rapid‐onset neonatal hypoglycaemia and jaundice. A balanced approach of fluid administration using colloids, crystalloids and vasopressors will be discussed.

Rationale for Prevention and Treatment of Glucose-Mediated Macrosomia: A Protocol for Gestational Diabetes

To formulate a rationale for preventing and treating hyperglycemia during pregnancy and the concomitant risk of macrosomia. We reviewed pertinent studies in the literature and personal experience with patients who had gestational diabetes. In addition, dietary and exercise interventions in the management of such patients were assessed. During pregnancy, sequential hormonal increases occur to provide glucose substrate to the fetus. When a pregnant woman has a limited insulin secretory capacity and cannot produce enough insulin to compensate for the effect of diabetogenic hormones, gestational diabetes occurs (usually during the second trimester). Maternal hyperglycemia reportedly increases fetal secretion of insulin, and fetal hyperinsulinemia may predispose the fetus to macrosomia. Thus, metabolic abnormalities associated with diabetes during pregnancy result in long-term effects on the offspring, including insulin resistance, obesity, and diabetes, which in turn may contribute to transmission of risk for development of the same problems in subsequent generations. Insulin therapy, dietary measures, and exercise have helped to achieve euglycemia in patients with gestational diabetes. Universal screening for gestational diabetes is optimally performed at 26 weeks of gestation. Treatment of diagnosed cases, by insulin, diet, and exercise regimens, will decrease the occurrence of glucose-related macrosomia, improve the outcome of the pregnancy, and reduce the risks for obesity, hypertension, and diabetes in future progeny.

Macrosomic infants of nondiabetic mothers and elevated C-peptide levels in cord blood

C-peptide concentrations in the cord blood of 29 macrosomic neonates born of nondiabetic mothers were higher than in 23 control infants whose birth weight was appropriate for gestational age, and there was a significant direct correlation between birth weight and C-peptide concentration. Six of the macrosomic infants studied (20%) had hypoglycemia in the first 24 hours of life, compared with none of the infants born with appropriate weight. We conclude that chronic fetal hyperinsulinemia may be one of the causes of macrosomia and neonatal hypoglycemia in infants of nondiabetic mothers. (J P EDIATR 1995;127:481-4)

Circulatory and metabolic effects of hypoxia in the hyperinsulinemic ovine fetus.

Fetuses of women whose diabetes is poorly controlled often exhibit hypoxemia and elevated catecholamine concentrations at birth. In the ovine fetus, experimental hyperinsulinemia results in hypoxemia, elevated catecholamine concentrations, and hemodynamic changes. Limited oxygen availability occurring during pregnancy-related complications and/or delivery may present an additional risk to the hyperinsulinemic fetus. In this study, we tested the hypothesis that hypoxia induced via acutely limiting oxygen availability compromises the hemodynamically and metabolically stressed but compensated hyperinsulinemic ovine fetus. Fetuses receiving insulin (n = 8) or placebo (n = 5) for 48 h were exposed to maternally induced hypoxia. Hypoxic hypoxia was associated with a surge in catecholamines in the hyperinsulinemic fetuses. During hypoxia, this group exhibited insulin-related sustained increases in the combined ventricular output and fetal body blood flow, accentuation of the prior insulin-related increase in blood flow to the heart, decreased systemic oxygen delivery, accentuation of the insulin-related increased oxygen extraction, reductions in the insulin-related increased systemic oxygen uptake, sustained increases in regional oxygen delivery to the heart and adrenal glands, reductions in the insulin-related increased delivery to the carcass, and decreased oxygen delivery to the kidneys and gastrointestinal tract. We conclude that, in the hyperinsulinemic ovine fetus, hypoxic hypoxia attenuates the hyperinsulinemia-mediated increased systemic oxygen uptake. Regional oxygen transport is preserved to vital regions (brain, heart, and adrenal glands) by increased perfusion and compromised to certain other regions (kidneys and gastrointestinal tract), because the increases in perfusion are insufficient to offset the limited oxygen availability.

Placental transferrin receptor in diabetic pregnancies with increased fetal iron demand.

Augmented fetal hemoglobin synthesis during diabetic pregnancy increases fetal iron demand. To study the effect of increased fetal iron demand on placental transferrin receptor (TR), we utilized a monoclonal antibody to localize placental TR immunoreactivity and 125I-labeled transferrin to study TR binding characteristics in 10 placentas from poorly controlled diabetic mothers with increased fetal iron demand and 10 placentas from nondiabetic mothers. The infants born to the diabetics had higher cord serum C-peptide, erythropoietin, and hemoglobin concentrations, indicating fetal hyperinsulinemia and hypoxia, with augmented erythropoiesis and iron demand. TR immunoreactivity was localized to the syncytiotrophoblast in both groups, was greater in the diabetic group, and was inversely correlated with fetal storage iron (r = -0.75; P < 0.001). Scatchard analysis of 125I transferrin binding data confirmed greater receptor number (Bmax 17.9 +/- 2.2 vs. 12.6 +/- 1.3 pM/mg protein, P = 0.05), but reduced binding affinity [dissociation constant (Kd) 7.6 +/- 0.9 vs. 5.4 +/- 0.4 nM/l, P = 0.03] in the diabetic group. The TR staining intensity, Bmax, and Kd were each correlated with cord C-peptide, suggesting either a primary or secondary role for fetal hyperinsulinemia in TR expression. This study provides in vivo evidence that fetal factors, such as iron demand or hyperinsulinemia, influence regulation of placental TR in humans. The increase in placental syncytiotrophoblastic TR expression associated with reduced cord serum ferritin concentration suggests that the fetus utilizes both increased placental iron transport and mobilization of fetal iron stores to support augmented fetal erythropoiesis.

Hyperinsulinemia and Macrosomia in the Fetus of the Diabetic Mother

To determine 1) whether macrosomia in the fetus of the diabetic mother is related to fetal hyperinsulinemia and 2) whether hyperinsulinemia and macrosomia are related to maternal metabolic control. Normal pregnant women (n = 95) were compared with insulin-treated pregnant women (n = 155), who were subdivided according to White's class, hypertension, and mode of delivery. All women were treated to achieve optimal metabolic control. HbA1c was determined at each visit. At delivery, umbilical plasma was analyzed for glucose, insulin antibodies, total insulin, free insulin, C-peptide, proinsulin components, and total and individual amino acids. Macrosomia, defined as > 2 standard deviation units (97.75%), was found in 10-27% of the diabetic groups. It was not related to maternal mass or size, but was significantly correlated with umbilical total insulin, free insulin, and C-peptide. Proinsulin components were not different among groups. Amino acids also were not different. Glycosylated hemoglobin was a weak predictor of birth weight and fetal hyperinsulinism. Macrosomia in the fetus of the diabetic mother remains inadequately explained. In a large population of pregnant women with strict metabolic control, macrosomia was mainly independent of glycosylated hemoglobin. Nevertheless, fetal hyperinsulinism remains the driving force for excessive fetal growth. The stimulus for fetal insulin excess in humans remains to be defined.

10 Managing diabetic patients with nephropathy and other vascular complications

Since the metabolic changes in normal pregnancy are diabetogenic, pregnancy imposes a severe stress on the metabolic milieu of diabetic patients. Moreover, many patients with long-standing diabetes have vascular complications, including retinopathy, renal insufficiency, nephrotic syndrome and hypertension, all representing separate risk factors for optimal fetal development. Recent experience has suggested that maternal hyperglycaemia, and associated fetal hyperinsulinaemia, may represent an important factor in the development of fetal complications. During the past two to three decades the incidence of perinatal deaths in all categories of diabetics has been reduced to a level that approaches the rate in healthy gravidas when severe congenital anomalies are excluded. Fetal and neonatal morbidity have also been reduced, although rates of congenital anomalies, hydramnios and respiratory distress syndrome remain high. Although the morbidity associated with oedema formation and hypertension is elevated, with meticulous management of patients with diabetic nephropathy, especially in the absence of severe renal insufficiency and/or severe hypertension, pregnancy performance and outcome can be similar to that of other insulin-dependent diabetic patients.

Metabolic interactions of diabetes and pregnancy.

Many of the embryonic and fetal abnormalities that occur in pregnancies complicated by maternal diabetes are the result of development in a metabolically abnormal environment. Diabetic embryopathy (birth defects and spontaneous abortions) results from maternal metabolic abnormalities during the first 6-7 weeks of gestation. The embryopathy appears to be multifactorial in origin, and the resulting defects remain important causes of morbidity and mortality in diabetic pregnancies. Diabetic fetopathy (predominantly macrosomia and neonatal hypoglycemia) results from fetal overnutrition and hyperinsulinemia during the second and third trimesters. Fetopathy may cause significant morbidity not only in the perinatal period, but also in later life as overweight infants grow up to be overweight children and young adults. Careful regulation of maternal metabolism from the preconceptional period onward can reduce greatly or even eliminate the excess risks that have been incurred by infants of diabetic mothers in the past. Successful management of maternal diabetes requires knowledge of the alterations in intermediary metabolism that normally occur during pregnancy, as discussed in this chapter.

Circulatory and metabolic effects of anemia in hyperinsulinemic ovine fetuses.

Infants born to women with poorly controlled diabetes mellitus have an increased incidence of perinatal asphyxia, cardiovascular abnormalities, elevated catecholamines, and sudden fetal death. Although hyperinsulinemic fetuses of diabetic women often exhibit polycythemia, they may also develop anemia because of pregnancy- and/or delivery-related complications. Experimental fetal hyperinsulinemia results in cardiovascular changes and a surge in catecholamines. We hypothesized that reductions in fetal O2 availability via anemic hypoxia limits O2 transport and compromises the hemodynamically and metabolically stressed but compensated hyperinsulinemic fetus. Chronically catheterized fetuses receiving insulin (n = 9) or placebo (n = 5) for 48 h were rendered anemic by an isovolemic exchange transfusion. In the hyperinsulinemic state, anemic-hypoxia augmented the insulin-mediated surge in norepinephrine concentration and increases in blood flow to brain, heart, and adrenal glands. Insulin-related increase in the combined ventricular output was sustained during anemia. O2 delivery to the fetus decreased, extraction increased, and O2 uptake did not change. Regional O2 delivery to the brain, kidney, gastrointestinal tract, muscle, fat, pancreas, spleen, and carcass decreased. Hyperinsulinemic ovine fetus exposed to anemic hypoxia demonstrated an accentuated surge in norepinephrine, a sustained increase in the combined ventricular output, preservation of systemic O2 uptake, and compromised regional O2 delivery to certain vascular regions. We conclude that the hyperinsulinemic fetus was able to compensate for anemic hypoxia by increased or sustained regional vascular perfusion.

Hypoxia-Induced Sympathetic Inhibition of the Fetal Plasma Insulin Response to Hyperglycemia

Large-for-delivery date babies, considered characteristic of diabetic pregnancy, are believed to result from fetal hyperinsulinemia. Paradoxically, infant birth weights tend to be low-for-delivery date in mothers with more severe diabetes. We tested the hypothesis that hypoxemia in such fetuses leads to sympathoadrenal stimulation and inhibition of insulin secretion; and, thus, produces a net reduction in the growth-promoting effects. Fetal sheep were prepared with chronic peripheral and adrenal cannulas. Fetal blood gases, lactate, norepinephrine, and epinephrine secretion rates; and plasma norepinephrine, glucose, and immunoreactive insulin concentrations were determined at 30-min intervals during a 2-h baseline period and a 4-h period of hyperglycemia divided into 2-h segments of hypoxemia (with and without alpha-blockade) and hyperoxia. Hypoxemia-hyperoxia sequences were varied randomly. Well-oxygenated fetuses responded to a threefold increase in glucose with a sixfold increase in plasma immunoreactive insulin. With hypoxemia, norepinephrine and epinephrine secretion were elevated and the insulin response was blocked. With hypoxemia and phentolamine blockade, the insulin response was enhanced with a 10-fold increase above baseline. In severe maternal diabetes with vascular disease or with poor control and very high glucose levels, the fetus is likely to be relatively hypoxemic. Our experiments suggest that in this situation, the fetal insulin response to hyperglycemia will be attenuated; this effect is mediated, at least partly, through sympathoadrenal stimulation.

Circulatory and metabolic effects of beta-adrenergic blockade in the hyperinsulinemic ovine fetus.

Offspring of women with poorly controlled diabetes exhibit hypoxemia, elevated catecholamine concentration at birth, and an increased incidence of fetal death. Experimental fetal hyperinsulinemia results in increased catecholamine concentration and hemodynamic changes including increased combined ventricular output and vasodilation of select fetal organs. We hypothesized that insulin-induced catecholamine-mediated beta-adrenergic stimulation supports some of these hemodynamic changes in the hyperinsulinemic ovine fetus. To study this, 24 chronically instrumented fetal sheep receiving insulin for 24 h were exposed to beta-(propranolol),beta 1-(metoprolol), and beta 2-(ICI 118,551) adrenergic blockade. Insulin infusion resulted in hyperinsulinemic-hypoglycemia, a surge in epinephrine and norepinephrine concentration, and increases in the combined ventricular output and regional blood flow to the heart, adrenal glands, kidney, gastrointestinal tract, liver, fat, muscle, carcass, and placenta. In the hyperinsulinemic state, beta-adrenergic blockade was associated with significant reductions in the combined ventricular output and blood flow to fat, carcass, lungs, and the placenta; beta 1-blockade was associated with reductions in the combined ventricular output and blood flow to the lungs; and beta 2-adrenergic blockade was associated with reductions in blood flow to muscle and lungs. Because beta-adrenergic blockade was associated with reductions in placental blood flow during hyperinsulinemia, oxygen and glucose metabolism were also compromised. We conclude that in the hyperinsulinemic-hypoglycemic normoxemic ovine fetus, insulin-induced catecholamine-mediated hemodynamic changes are modulated in part by beta-adrenergic receptor stimulation.

Prenatal diagnosis of familial neonatal hyperinsulinemia

A kindred with familial neonatal hyperinsulinemia is described. Infant A was macrosomatic and stillborn. Infant B was macrosomatic at birth following a pregnancy uncomplicated by maternal diabetes. Following diagnosis of hyperinsulinemic hypoglycemia, this patient was treated with oral diazoxide. Therapy continued until hyperinsulinemia resolved by two years of age. Based on this history, the pregnancy with infant C was intensively monitored using ultrasonography and amniocentesis. Insulin and C-peptide concentrations in amniotic fluid were markedly increased compared to control pregnancies. Based on these results, infant C was delivered immediately upon obtaining evidence of lung maturation. Neonatal hyperinsulinemia was confirmed by a markedly increased cord plasma insulin concentration. Based on our experience, we recommend that insulin concentrations in amniotic fluid be used as an indicator of fetal hyperinsulinemia in kindreds with prior newborn hyperinsulinemic hypoglycemia. This information may be used to direct timing of delivery and therapy in the immediate postnatal period.